This invention pertains to an osmotic device containing diltiazem and an angiotensin converting enzyme (ACE) inhibitor. More particularly, it pertains to an osmotic device tablet which provides a controlled release of diltiazem and a rapid or immediate release of an ACE inhibitor diuretic compound.
ACE inhibitors, diuretics and calcium channel blockers are three types of antihypertensive agents used either as monotherapy or in combination to regulate blood pressure in the treatment of hypertension. The efficacy of ACE inhibitors is related to the initial level of plasma angiotensin II (Ang II) or plasma renin activity. However, patients with low plasma renin activity also experience a fall in blood pressure during ACE inhibitor therapy. In contrast to diuretics, diltiazem does not have adverse metabolic effects on electrolytes, carbohydrate metabolism and lipid metabolism. Diltiazem is particularly indicated in patients with hypertension and concurrent angina pectoris, diabetes, hyperlipidemias and chronic renal disease.
The commercially available product TILAZEM(trademark) (Parke-Davis) is a sustained release form of diltiazem. It has been reported to provide an adequate therapeutic benefit but causes unwanted side effects.
While each type of drug has demonstrated efficacy in the clinic, combinations of a calcium channel blocker with an ACE inhibitor or a diuretic are more effective, i.e., the drugs typically exhibit additive, if not synergistic, therapeutic benefits. Clinical trials have documented the augmentation of blood pressure reduction when these agents are combined as compared to the individual agents. In addition, clinical results have shown that combination therapy may be effective even in situations where each agent alone is ineffective.
The calcium channel blocker and ACE inhibitor can be administered in single or multiple dosage forms. Single dosage unit combination tablet and capsule dosage forms containing a combination of diltiazem (DZ) with an ACE inhibitor, such as enalapril (ENA), captopril (CAP), or lisinopril (LIS), are known. These combination dosage forms generally provide a rapid release of the ACE inhibitor and a controlled release of DZ. These tablets are generally made for once- or twice-daily administration.
The commercial product TECZEM(trademark) is a combination product providing an extended release form of diltiazem and an immediate release form of enalapril. This combination therapy has; been shown to be more effective than either agent alone in treating patients that do not respond well to either agent individually. The product has been associated with side effects such as dizziness, headache, cough, rash, asthenia, fatigue, impotence, edema/swelling, among other adverse events. These side effects usually begin shortly after administration of a unit dose and may continue upon chronic administration depending upon a physician""s ability to titrate the dose for the patient. The discomforts of cough, dizziness and headache in a patient generally cause insomnia in a patient.
Osmotic devices and other tablet formulations are known for their ability to provide a controlled release of a wide range of drugs. Such osmotic devices and other tablet formulations are disclosed in U.S. Pat. No. 4,968,507 to Zentner et al., U.S. Pat. No. 4,014,334 to Theeuwes et al., U.S. Pat. No. 4,576,604 to Guittard et al., Argentina Patent No. 234,493, U.S. Patent No. 4,673,405 to Guittard et al., U.S. Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502 to Ayer et al., U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No. 5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770 and Argentina Patent No. 199,301, the entire disclosures of which are hereby incorporated by reference. Osmotic devices containing diltiazem, such as the controlled porosity osmotic pump disclosed in U.S. Pat. No. 4,880,631 to Haslam et al., are also known.
While conventional sustained release dosage forms, such as described above, are effective, osmotic devices such as those described by Faour et al. (U.S. Pat. No. 6,004,582), Harris et al. (U.S. Pat. No. 4,472,380), and Cavero et al., the entire disclosures of which are hereby incorporated by reference, are particularly advantageous for delivering two different dosage forms from a single osmotic device tablet. Faour et al., Harris et al., and Cavero et al., however, do not disclose the specific combination osmotic device formulations claimed herein. Moreover, Faour et al., Harris et al., and Cavero et al. do not disclose osmotic devices that provide the specific plasma profiles or release profiles for the various different combinations claimed herein, nor osmotic devices having a drug containing external coat that has been spray coated rather than compression coated onto the device.
Mammals suffering from blood pressure related disorders generally require administration of specific amounts of a calcium channel blocker and/or ACE inhibitor at night while resting when the risk of suffering a cardiovascular event is highest. Accordingly, people suffering from these disorders generally stay up late or wake up in the middle of the night to take their medication. In addition, commercially available products do not currently address the issue of timed administration of the calcium channel blocker and/or ACE inhibitor.
Chronotherapy refers to the timed administration of therapeutically effective agents. For solid dosage forms, chronotherapy is achieved by the use of delayed release coatings to delay the release of one or more drugs until an approximately predetermined time period. It would be useful to develop a chronotherapeutic dosage form containing diltiazem and an ACE inhibitor. The prior art does not disclose a chronotherapeutic osmotic device having a delayed release of both the diltiazem and the ACE inhibitor or diuretic agent, wherein the release of diltiazem is controlled and the release of the ACE inhibitor is rapidly.
In one aspect, the present invention provides a chronotherapeutic osmotic device comprising:
a core comprising a therapeutically effective amount of diltiazem and at least one osmotic agent or osmopolymer, wherein the core provides a controlled release of diltiazem;
a semipermeable membrane surrounding the core and having a passageway there through; and
an external coat comprising a therapeutically effective amount of an angiotensin converting enzyme inhibitor or diuretic, wherein the external coat provides a rapid release of the ACE inhibitor or diuretic; wherein:
at least 80% of the DZ is released within 20 hours, and at least 45% of the ACE inhibitor is released within 40 minutes, or at least 75% of the diuretic is released within about 40 minutes, after exposure of the osmotic device to an aqueous solution; and
initial release of the DZ and optionally the ACE inhibitor or diuretic is delayed for a period of at least about 1.5 hours.
In some specific embodiments, the ACE inhibitor is selected from the group consisting of enalapril (ENA), captopril (CAP), lisinopril (LIS), benazepril (BEN), enalaprilat (ENAP), espirapril (ESP), fosinopril (FOS), moexipril (MXP), quinapril (QNA), ramipril (RAM) perindopril, and trandolapril (TND).
In other specific embodiments, the diuretic is selected from the group consisting of high-ceiling diuretics, furosemide, bumetanide, ethacrynic acid, torsemide, muzolimide, azosemide, piretanide, tripamide, chlorothiazide, hydrochlorothiazide, chlorthalidone, indapamide, metozalone, cyclopenthiazide, xipamide, mefruside, dorzolamide, acetazolamide, methazolamide, ethoxzolamide, cyclothiazide, clopamide, dichlorphenamide, hydroflumethiazide, trichlormethiazide, polythiazide and benzothiazide.
In still other specific embodiments, the external coat is applied by spray coating rather than by compression coating. By spray coating rather than compression coating the external coat, a thinner external coat, and therefore a smaller osmotic device, is formed.
Another aspect of the invention provides a method of treating hypertension in a mammal, the method comprising the step of administering an osmotic device which provides a controlled release of diltiazem from its core and a rapid release of an ACE inhibitor or diuretic from an external coat, wherein at least 75% of the ACE inhibitor is released within about 40 minutes, or at least 75% of the diuretic is released within about 40 minutes, and at least about 70% of the diltiazem is released within about 20 hours after administration.
In other specific embodiments, the osmotic device has: a) a diltiazem release profile similar to that shown in FIG. 1; or b) an ACE inhibitor or diuretic release profile similar to that shown in FIG. 2. In still other specific embodiments, the release of DZ and/or the ACE inhibitor or diuretic has a delayed onset of at least about 1.5 hours.
The osmotic device generally delivers the ACE inhibitor or diuretic to the upper GI tract and the diltiazem to the middle to lower GI tract.
Other features, advantages and embodiments of the invention will become apparent to those skilled in the art by the following description, accompanying examples.